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16 Nociception and Pain


1 Nociception and Pain, Birbaumer, Biological Psychology, DOI / _, Springer Medizin Verlag Heidelberg 2010

2 342 Chapter Nociception and Pain)) Case 1: As an infant, Christiane D. appeared completely normal to her surroundings. But she developed into an extremely irritable girl who ruthlessly hammered his head on the floor when she bursts angry, so that large bruises often formed. She often bit her tongue bloody while chewing. The tip of the tongue was finally missing completely. At the age of 3 she already suffered severe burns when she kneeled on a switched-on radiant heater for a long time. From her earliest childhood on, severe joint and bone inflammation occurred again and again. C. D. died when he was only 29 years old from severe infections that spread from the joints and bones to the entire body. She suffered from a complete innate insensitivity to pain. Case 2: In the now 55-year-old patient K.L., short episodes of pain occurred in the left cheek and the left corner of the mouth for the first time about 5 years ago, which became more and more frequent and agonizing in the further course. With every attack of pain, K. L. has the impression that his face is being pierced by a red-hot iron. Each pain attack only lasts a few seconds, but sometimes entire volleys of it occur. Since the seizures are caused by touching or moving the left corner of the mouth, e.g. B. can be triggered when washing, shaving, eating or speaking, the patient eats, drinks and speaks as little as possible. He perceives his life as torture and is thinking of putting an end to it. Mr. K. L. suffers from idiopathic trigeminal neuralgia, a rare but particularly severe and therapy-resistant form of chronic pain. On the one hand, the pain is indispensable for a normal life as a warner. On the other hand, chronic pain can make life hell in such a way that it is no longer worth living for those affected..1 Perceptual psychology of pain.1.1 Pain characterization Pain sensation and nociception According to a definition of the international pain society IASP, »pain is an unpleasant sensory and emotional experience that is associated with current or potential tissue damage or is described in terms of such damage «. According to this, pain is an elementary sensory sensation that is specifically triggered by the action of tissue-damaging (noxious) stimuli. This is connected with an unpleasurable emotional experience (Sect. 1.2). The definition also states that pain is always perceived as an expression of tissue damage, even if it is not (or no longer) present (Sect. 5.1). While pain is a conscious sensory and emotional experience, the term nociception encompasses the objective processes with which the nervous system absorbs and processes noxious stimuli. Toxic stimuli are mechanical, thermal or chemical stimuli that potentially or currently damage the tissue. Nerve cells involved in nociception are nociceptive neurons. Together they form the nociceptive system that is presented in Sections 2 and 3. Pain as a drive for avoidance Pain is usually discussed in the context of sensory physiology and perceptual psychology, but it differs fundamentally from all other sensory systems: pain, as it is also reflected in the above definition of pain, almost always has a motivational-emotional component, i.e. H. it acts as an impetus for avoidance (chapter 26). This means that the emergence of pain cannot only be understood physiologically, but only with the inclusion of the psychophysiology of drive and feeling (Chapters 26 and 27). This is v. a. for chronic pain, but also applies to acute pain conditions, such as B. extensive injuries. G Pain is an independent sensory modality that is mediated by an independent peripheral and central nervous apparatus, the nociceptive system. Pain, especially chronic pain, always acts as a drive to avoid it. Somatic and visceral pain Pain (synonym: sense of pain) can be divided into a number of qualities with regard to where it originates. In. Fig.1 these qualities are shown in the red boxes. The pain modality initially comprises the two qualities of somatic and visceral pain. If the somatic pain comes from the skin, it is called surface pain; if it comes from the muscles, bones, joints and connective tissues, it is called deep pain. Surface and deep pain are therefore subqualities of somatic pain. If you prick the skin with a needle to trigger a surface pain, you feel a pain of a "light" character, which can be easily localized and which quickly subsides after the stimulus has ceased. This first pain of the needle stick is often followed by a second pain of a dull (burning) character, which is more difficult to localize and only slowly subsides, with a latency of 0.5 1.0 s. This pain can be triggered particularly well by squeezing an interdigital fold.

3 .1 Perceptual Psychology of Pain 343 Box.1. The theory of specificity of pain Today it is assumed that pain is an independent sensation. This was doubted in the 19th century and well into the 20th century. One of the pioneers of the specificity theory of pain was the Würzburg physiologist Max von Frey (), who found out with the hair and spiked bristles that he used, which is still used today for testing skin sensitivity, that the skin is analogous to the findings of mechano and thermoperception is also not equally sensitive to the pain, but has pain points. These are significantly more common than pressure points. Since the cold and warm points of the skin are even less numerous than the pressure points, the ratio of the pain points to these is even greater. Based on these findings, it seemed likely that pain has its own sensors, i.e. special nociceptors, that nociception is not mediated via mechano or thermoreceptors (as was required by the various intensity and pattern theories at the time). G The pain modality comprises the two qualities of somatic and visceral pain. Somatic pain is surface pain and deep pain that originates from the skin or deeper tissues. Visceral pain originates from the bowels. The nature of the pain typically depends on the place of origin of all pains. Fig..1. Qualities of pain according to their place of origin. The qualities are highlighted with red and orange tones, the places of origin green. Examples of pain are given below on a light blue background (details 7 text) The deep pain is of a dull pain character, it is usually difficult to localize and it tends to radiate into the environment. We know such pain as joint pain, for example, which is one of the most common forms of pain in humans. In addition to somatic pain and its subqualities,. Fig. 1 Another important pain quality is visceral or intestinal pain. Such pain occurs, for example, when the hollow organs are stretched rapidly and heavily (e.g. the gall bladder or the renal pelvis, 7 above). Furthermore, spasms or strong contractions are painful, especially if they are associated with a lack of blood flow (ischemia). Acute and chronic pain In addition to the place of origin, the duration of a pain is an essential aspect for its assessment. In acute pain, for example in an accident, appendicitis or dental caries, the pain is usually limited to the location of the damage, this location can be clearly localized for us, and the extent of the pain depends directly on the intensity of the stimulus. These pains indicate an impending or already occurred tissue damage. So they clearly have a signaling and warning function (case 1 in the introduction). Once the damage has been removed, they quickly subside. In addition to acute pain, there are numerous pains that persist for a long time (e.g. back pain, tumor pain) or recur at more or less regular intervals (e.g. migraine headaches, heart pain in angina pectoris, trigeminal neuralgia). These forms of pain, constant pain and recurring pain, are summarized as chronic pain. Generally will

4 344 Chapter Nociception and Pain pain is only considered chronic if the symptoms persist for more than six months. From a sensory physiological point of view, there is often no clear relationship between the extent of organ damage and the pain intensity in chronic pain, v. a. if the pain persists for a long time (case 2 in the introduction). In other words, with chronic pain, over time there is often a significant detachment of the pain experience from the original underlying disorder. This "independence" makes chronic pain appear as an independent disease syndrome that clearly stands out from acute pain. A physiological task can usually not be ascribed to chronic pain. Seen in this way, a lot of chronic pain is pointless and should therefore be alleviated. However, it should not be overlooked that chronic pain can have a social function that at least in some cases prevents pain relief, e.g. B. if this would threaten the social structure in which the pain sufferer lives (Sect. 5.2). G A distinction is made between acute and chronic pain according to the duration of the pain. Acute pain is an indispensable warning sign for a normal life, chronic pain, on the other hand, is often pointless. 1.2 Pain components Sensory components When a hand is immersed in water above 45 C, nociceptors (Section 2.1) of the skin are stimulated. Their afferent impulses convey information about the localization of the heat stimulus, about its beginning, its intensity (which depends on the water temperature) and about its end as soon as the hand is pulled out of the water. We become aware of this information as a sensory perception as well as other sensory impressions, for example if we dipped our hand in lukewarm or cool water and thus triggered a warm or cold sensation. We call this aspect of pain the sensory or sensory-discriminative component of pain (. Fig. 2). Affective component If, to stay with the example, we immerse ourselves in a bath of 25 C on a very hot summer's day, we not only feel a cold stimulus on the skin, but the cooling also triggers a pleasant feeling of refreshment in us at the same time. However, on a cold winter day, the same bathroom would be perceived as uncomfortably cool. A sensory impression can, depending on the initial situation and circumstances, evoke feelings of pleasure or discomfort in us. This applies to practically all sensations, e.g. B. from the eye, from the ear, from the smell or from the taste. Pain is an exception. It almost always only triggers unpleasant affects or emotions in us, our well-being is disturbed by it, in short, the pain hurts, we suffer from it and try to avoid it (Sect. 1.1). We refer to this aspect of pain as the emotional or affective component (chap. 27). Vegetative component Immersing the hand in hot water not only causes pain and discomfort, but also leads to the expansion of the skin vessels and thus increased blood flow. Fig..2. Schematic representation of the components of pain activated by noxious signals. In the resulting pain assessment (cognitive component) and pain behavior, the sensory, affective and vegetative components are included to varying degrees, depending on the type of pain. Conversely, the assessment and behavior of pain in turn influence the expression of the affective and vegetative pain components. The scheme also applies to pain that is not caused by nociceptors or neuralgic excitations

5 .1 Perceptual psychology of pain 345 visible in the reddening of the skin. Conversely, immersion in ice water constricts the skin vessels and blood flow decreases accordingly. In both cases, blood pressure tends to rise, heart rate increases, pupils dilate, and breathing changes. These reactions to the painful stimulation are reflexively handled by the autonomic or vegetative nervous system, we therefore speak of the autonomous or vegetative component of the pain process. The vegetative component can be very pronounced, especially in visceral pain. B. in a biliary colic, as nausea with vomiting, sweating and a drop in blood pressure. Motor component After all, we are well acquainted with the fact that if a hand is unintentionally immersed in hot water or touched a hot stove top, the hand jerks back long before we became aware of heat pain and could have arbitrarily reacted to it. This motor component of pain is known to us as the escape or protective reflex in a large number of examples (Chapter 13). She plays v. a. plays an important role in external noxious stimuli. But even with deep pain and visceral pain, motor components, e.g. B. in the form of muscle tension can be observed. In a broader sense, other behavioral expressions of the pain, for example facial expressions, lamentations or voluntary movements, which result from the pain assessment (7 below), are to be regarded as motor or better psychomotor components of the pain (. Fig. 2, lower right half of the picture). G The sensory experience of pain is accompanied by affective, vegetative and motor reactions of the body. The latter two run reflexively via the autonomic and motor nervous system, they can usually not be influenced arbitrarily. 1.3 Pain assessment Contributions of the various pain components to the pain assessment. For example, perceiving it as mild, unpleasant, disturbing, violent or unbearable is determined by the sensory, affective and vegetative components of the pain to a varying extent depending on the cause of the pain and accompanying circumstances (. Fig. 2). For example, in the case of acute surface pain, the sensory component will often be in the foreground, in the case of acute visceral pain the vegetative component will play a major role, and in the case of chronic pain the affective component will often be decisive for the pain assessment. Contribution of the pain memory to the pain assessment The decisive factor for the pain assessment is v. a. that the current pain is measured against the pain experiences stored in the short and long-term memory and evaluated according to these experiences (Sect. 5.2). The pain rating can therefore be referred to as the cognitive or cognitive component of pain. It happens in parallel with the processing of the 4 pain components described above and can therefore take place very quickly, both consciously and consciously. The result of this cognitive process influences all 4 pain components and leads to corresponding expressions of pain (psychomotor components, e.g. facial expressions, wailing, desire for pain reliever medication). So it flows into the expression of the affective, vegetative and motor components, i.e. H. These components are not only important for the assessment of the pain, but their extent also depends on the overall assessment of the current pain: We suffer more from a pain that we consider "important" to our wellbeing than from one that is seems banal to us (with the same intensity). G The various pain components contribute to the pain assessment to different degrees depending on the circumstances. The pain memory is also significantly involved in this. Social context of the pain assessment A number of other factors are included in the pain assessment and the resulting expressions of pain, which are only briefly referred to here. The extent of individual pain components depends on e.g. For example, it depends a lot on the current social situation, family background, upbringing and also on ethnic origin. A North American Indian on the torture stake behaves completely differently when it comes to expressing pain than a southern Italian housewife with biliary colic, even if both suffer from pain of the same intensity. G Pain assessment and the resulting pain expression also depend on the social environment in which the pain occurs. Psychological context of the pain assessment In addition, the circumstances under which a pain event occurs are often decisive for a pain assessment. It is well known that war wounds require less painkillers than comparable injuries in civilian life. Apparently, the prospect of going home soon and the happiness of having survived the battle diminishes the pain

6 346 Chapter Nociception and pain perception and assessment to a considerable extent. Contrary to expectations, however, there were only weak associations between pain behavior and persistent personality traits (such as a comparison between extroverted versus introverted persons). An analysis of the personality variables can hardly be used to make a useful prediction of pain behavior. Pain learning in early childhood Appropriate behavior and emotionally normal reactions to painful stimuli are apparently for the most part not innate, but must be learned by the adolescent organism at an early stage of its development.If these early childhood experiences are absent, they are difficult to learn later: young dogs that were protected from all harmful stimuli in the first 8 months of life were unable to react appropriately to pain and learned this only slowly and imperfectly. Again and again they sniffed open flames and let needles stick deep into their skin without showing anything more than local reflex twitches. Similar observations were also made on young rhesus monkeys. G The pain assessment also depends on the psychological context under which the pain stimulus acts. B. "hurts" less than comparable civilian injuries. Pain behavior must be learned from an early age..1.4 Pain measurement Subjective algesimetry The classical methods of psychophysics can also be applied in humans to the experimental study of the relationships between noxious stimuli and pain, whereby both subjective and objective methods are used in this experimental algesimetry. Thermal, electrical, mechanical and chemical stimuli can be used to trigger pain. In subjective algesimetry, 4 the pain threshold is measured, i.e. the stimulus intensity at which a pain sensation occurs, 4 the pain intensity (which is expressed verbally or via another display method, section, intermodal intensity comparison) and finally 4 the pain tolerance threshold, i.e. the stimulus intensity , in which the test subject demands the termination of the stimulus. Figure 3 shows as an example the measurement of the subjective pain intensity when a heat stimulus is applied. Fig. 3. Pain measurement in humans when a heat stimulus is applied to the skin. The lower curve shows the rise and fall of the stimulus temperature (by 1 C per second), the upper curve shows the pain intensity the test subject indicates on a visual analog scale (VAS). The sensation of pain begins at 42 C, increases with increasing temperature and goes back to the skin with increasing intensity when the irritation temperature decreases. The pain intensity is indicated on a visual analog scale (VAS), with the two endpoints of the VAS being defined as “no pain” and “unbearable pain”. Measuring pain adaptation In addition to pain intensity, clinical v. a. it is still important whether the pain sensation adapts. The subjective experience tends to indicate a lack of adaptation (e.g. headache or toothache lasting for hours). Even with the experimental measurement of pain adaptation in heat pain (. Fig. 4), there are no indications of pain adaptation. The decrease in the pain threshold temperature in the course of the measurement actually indicates a sensitization of the nociceptors in the irradiated skin area due to the persistent heat stimulus. (With repeated, everyday nociceptive stimuli and electrical pain stimuli, however, a habituation can usually be observed.) Objective algesimetry Objective algesimetry uses v. a. the measurement of motor and vegetative reactions to the pain and the registration of evoked cortical potentials (the term "objective" only means that not the "subjective" statements of the test person, but the variables registered by the observer are measured). Fig. 5 shows the narrow Relationship between subjectively experienced pain intensity and the amplitude of the evoked cortical potential ms after application of an electrical pain stimulus to the thumb. Different methods are often used (e.g. measurement of evoked potentials with simultaneous measurement of the pupil diameter as a measure of the sympathetic tone), often subjective and objective

7 .2 The peripheral nociceptive system 347. Fig. 4. Experimental measurement of the thermal pain threshold. Infrared rays heat a blackened area of ​​skin on the subject's forehead. The skin temperature is recorded by a temperature sensor (photocell) and recorded on a recorder. The red curve shows the dependence of the pain threshold (mean values ​​of numerous people) on the duration of the heat stimulus. The test subjects were asked to regulate the radiation intensity themselves in such a way that the skin temperature was just perceived as painful for the duration of the test. The initial overshooting of the skin temperature beyond the pain threshold is due to the inertia of the experimental set-up, combined with methods (multidimensional algesimetry). Experimental algesimetry is currently a rapidly growing field of work from which essential information about the nature of pain can still be expected. Clinical algesimetry Clinical algesimetry uses ratio estimation methods on the subjective level on the one hand, such as the VAS described above, in which the patient enters the extent of his pain between 2 endpoints (no pain / unbearable pain) at different times. On the other hand, questionnaires are used, such as the widely used McGill-Pain Questionnaire by Ronald Melzack. Finally, the clinical pain intensity can also be related to an experimental pain, for example when determining the tourniquet pain quotient, in which the patient estimates the intensity of an experimental ischemic muscle pain in comparison to his or her clinical pain (Sect.). G With the help of objective and subjective algesimetry, pain threshold, pain intensity, pain tolerance threshold and the course of pain adaptation in humans can be measured. Fig..5. Pain-evoked event-related brain potentials. The red curves show the answers to increasingly intense pain stimuli. To the right of this, the subjective assessment by the test subjects is given. The event-related potential is proportional to the subjectively experienced pain intensity.2 The peripheral nociceptive system.2.1 Structure and function of the nociceptors Structure of the nociceptors Practically all human tissues are innervated by special sensors that have such a high threshold that they can only be detected by tissue-damaging or threatening ones Stimuli (»noxes«, Latin noxa = damage) are aroused. These receptors are called nociceptors (synonymous: nocisensors). Your excitement usually triggers pain,

8 348 Chapter Nociception and Pain. Fig..6a c. Structure and function of a nociceptor. a Schematic longitudinal and cross-section of the sensory termination of a nociceptive C-fiber (green). The axon is covered by Schwann cells (blue), but in the swellings the axon has direct contact with the environment. b Schematic representation of a nociceptor with 2 receptive fields. When the receptive fields are stimulated, action potentials are triggered that can be tapped on the axon. The electrical stimulation of the axon is used to determine the conduction velocity. c Responses of a polymodal nociceptor to noxious pressure, noxious heat and chemical irritation with bradykinin, which in turn signal that either external stimuli (e.g. heat) or internal stimuli (e.g. inflammation) threaten to harm the body. Histologically, the nociceptors are non-corpuscular (free) nerve endings that branch widely in the tissue starting from a single afferent nerve fiber. A schematic longitudinal and cross section through the final structure of a nociceptor is shown in Fig. 6a. Most of the nociceptors have unmyelinated axons (C fibers, conduction speed around 1 m / s, Table 2.1 in Section), some of the nociceptors have thin myelinated axons (Aδ fibers, conduction speed 2.5-30 m / s). Response behavior of the nociceptors So far, mainly nociceptors have been found in human skin that respond to mechanical (e.g. needle stick, squeezing) as well as thermal (heat, cold) and chemical stimuli (e.g. bradykinin, prostaglandin). So these nociceptors are polymodal. Also in the skeletal muscles, their tendons and in the joint tissue predominantly polymodal nociceptors appear. Figure 6b shows the technique of deriving action potentials of a nociceptor in animal experiments and. Fig. 6c his response to mechanical, thermal and noxic stimuli. The. Fig. 7 illustrates the response behavior of a human polymodal nociceptor to a variety of stimuli (7 legend). There are also nociceptors, albeit in smaller numbers, that respond to only one form, sometimes 2 form. Fig..7a i. Response behavior of a single polymodal nociceptor; Derivation on awake people. The impulse activity was recorded with a transcutaneous metal microelectrode on the peroneal nerve at knee joint level while skin stimulation of the receptive field on the big toe was performed. a response to a single electrical stimulus. b Irritation with a Von Frey hair of 2 g. This stimulus was felt as a tingling sensation 2 s after the start. c Repeatedly stroking the receptive field firmly with a thin pencil leads to slight pain. d Irritation with a stick (15 g weight) is felt as pressure. e Pressure with a pointed stick of 5 g causes slight pain. f A pinprick evokes first and second pain. g Application of itching powder to the receptive field leads to burning itching. h Contact with nettles causes pain followed by itching. i A hot thermode leads to an initial sharp pain which later becomes burning From Torebjörk HE (1974). Courtesy Wiley-Blackwell.

9 .2 The peripheral nociceptive system 349 men noxic stimuli, e.g. B. specific mechanonociceptors or heat nociceptors or mechano-heat nociceptors respond. Another subgroup of nociceptors consists of sensory nerve fibers that, under normal conditions, cannot be excited by mechanical or thermal stimuli. They are called silent or "sleeping" nociceptors (for "waking up" 7 below). In the human skin, they account for 20-30% of the nociceptors (no quantitative estimates are yet available for other tissues). G Most nociceptors have non-corpuscular (free) endings. Nociceptors are mostly polymodal; small subpopulations are more specific. All tissues are also innervated by silent "sleeping" nociceptors. Plasticity of the response behavior of nociceptors As illustrated in Fig. 8a, numerous molecules are formed in inflamed tissue in various inflammatory cells, in thrombocytes and in the plasma and then released, which are collectively referred to as inflammation mediators. Most of these mediators, such as B. the prostaglandins act on polymodal nociceptors in such a way that their thresholds are lowered and their sensitivity is increased. This sensitization has the effect that the nociceptors are already excited by normally non-noxious stimulus intensities (touch, warmth), and their responses to noxious stimuli increase (. Fig. 8b). Subjectively, there is an increased sensitivity to pain in the inflamed area (the simplest example is sunburn). In addition, many nociceptors develop spontaneous activity in the inflamed area. This is the basis for resting pain. In addition to the polymodal, silent nociceptors are also sensitized. This makes them excitable to mechanical and thermal stimuli and increases the nociceptive influx into the spinal cord. Sensitization of silent nociceptors is also an important neural mechanism of visceral pain, e.g. B. Angina pectoris (heartache from contraction in ischemic conditions). G inflammation mediators, such as B. Prostaglandins, sensitize nociceptors and induce spontaneous activity. "Sleeping" nociceptors "wake up" through the sensitization and thereby increase the nociceptive afferent influx into the CNS. Efferent effects of nociceptors; neurogenic inflammation nociceptors are, on the one hand, afferent communication channels (7 above). On the other hand, when their arousal be off. Fig..8a, b. Sensitization of a nociceptor in inflammation. a Formation and release of inflammatory mediators from inflammatory cells, platelets and the plasma. These form an inflammatory chemical environment in the area of ​​the sensory nerve endings. b Lowering of the response threshold of a nociceptor in the course of the sensitization process: the nerve endings become so sensitive to mechanical and thermal stimuli that even normally non-noxious stimuli stimulate the fibers. Their peripheral endings release neuropeptides (e.g. substance P, SP, or »calcitonin gene -related peptide «, CGRP). These neuropeptides cause a local widening of the small blood vessels (vasodilation, visible on the skin as reddening and a rise in temperature) and the escape of blood plasma into the tissue (plasma extravasation, impressed as edema). At the same time, these neuropeptides help sensitize the nociceptors. As a neurogenic component, these 3 processes increase the effect of the local inflammation mediators and thus influence the course of the inflammation. G The release of neuropeptides such as SP and CGRP from activated nociceptors leads to vasodilation, plasma extravasation and nociceptor sensitization (neurogenic inflammation). 2.2 Molecular biology of nociceptor function Ion channels and receptors in nociceptive endings. Fig. 9 shows in a schematic overview all the ion channels and receptors of the terminal region of nociceptors known to date or probable for good experimental reasons. For further loading

10 350 Chapter Nociception and Pain. Fig. 9. Ion channels and receptors for mediators in nociceptors. Above: Representation of the receptors for mediators. Bottom: Representation of the suspected equipment on ion channels. The circles in the ending represent vesicles filled with messenger substances. Mediators that are released from different cells act on the receptors in the ending. Gp130 glycoprotein 130 (component of receptors for cytokines), Trk tyrosine kinase receptor, 5-HT serotonin receptor, EP prostaglandin E receptor, B bradykinin receptor, P2X purinergic receptor for ATP, H histamine receptor, adrenergic substance 1 receptor, NK1 neurokinin P, CGRP “calcitonin-generated peptide” receptor, SST somatostatin receptor, TTX tetrodotoxin, VR1 vanilloid-1 receptor, VDCC (“voltage-gated calcium channels”), voltage-gated calcium channels. Please note: most endings only have a part of the presented receptor speech.It should be noted that not all receptors and ion channels occur on all nociceptor terminals, but only a certain selection, depending on the type of polymodality or specificity, as is to be expected from the response behavior of the various nociceptor types (Section 2.1). The membrane receptors for mediators are arranged at the top of the figure, the ion channels at the bottom. The tissue mediators that are also entered activate and / or sensitize the nociceptive terminals via the membrane receptors. Many of the receptors, such as B. those for prostaglandins, pass on their effect via G-proteins (section on the mechanism of action). Others, such as B. for serotonin) are directly occupied with ion channels. G Numerous receptors and ion channels are built into the membrane of the nociceptor terminal, whereby the respective equipment of a nociceptor determines its more or less specific modality. Transduction in nociceptors The following molecular biological picture currently emerges for the transduction of noxious stimuli: 4 mechanical noxae, i. H. mechanical stimuli of high intensity, open mechanosensitive, unspecific cation channels. a. the terminal membrane is depolarized by Na + ions. 4 chemical noxae, such as B. bradykinin and the prostaglandins already mentioned mediate their sensitizing and / or excitatory effect via G-protein-coupled receptors (7 above). 4 Tissue acidification activates specific sodium-permeable ion channels (ASIC, "acid sensing ion channel") as well as the vanilloid receptor mentioned below and thus leads to sensitization or excitation. 4 heat stimuli activate the vanilloid receptor, VR-1, which is also sensitive to acid stimuli (7 above) and to the active substance of the bell pepper, capsaicin. Membrane proteins similar to VR-1 are grouped together as the TRP family (from "transient receptor potential"). 4 cold stimuli lead to the closure of potassium channels, which net also leads to the depolarization of the terminals. G Noxic stimuli act via receptive membrane proteins in such a way that the nociceptor membrane is depolarized and thus sensitized or excited. Some stimuli act directly on ion channels, others activate them via G-protein mediation. Transformation in nociceptors As everywhere in excitable membranes, voltage-controlled sodium, calcium and potassium ion channels are also embedded in the terminal membranes of the nociceptors (. Fig. 9, bottom left). If a sufficiently large sensor potential is triggered by the transduction of noxious stimuli (Section), these ion channels open and v. a. by the influx of sodium ions, for the formation of action potentials, which is known as transformation (Sect.). Most voltage-gated sodium channels (for structure and mode of operation, Sect.) Can pass through

11 .3 Central Nociceptive Systems 351 the poison of the buffer fish, the tetrodotoxin, TTX, can be blocked. But there are also TTX-resistant voltage-controlled ion channels. These are particularly common in nociceptors and are therefore also in the. Fig. 9 drawn in. (Blocking the TTX-resistant channels could possibly reduce the excitability of the nociceptors, i.e. serve as a pain reliever). G Above-threshold sensor potentials lead via the activation of voltage-controlled ion channels to the transformation of the sensor potentials into action potentials, whereby TTX-resistant Na channels are involved in an above-average number The skin and the transitional mucous membranes can be released.With appropriate technology, it is possible to produce all degrees of itching without pain and vice versa. According to these findings, itching is possibly a sensation independent of pain. On the other hand, there was and there is also evidence that the sensation of itching is only a special form of pain sensation that occurs in certain irritative states. This is supported by the fact that a series of itching sensations with stronger stimulus intensity apparently lead to pain sensations and that an interruption of the nociceptive anterior tracts of the spinal cord is accompanied by a loss of itching sensation. Pruritus receptors in the human skin Using the technique of transcutaneous microneurography (Sections and), a German-Swedish working group has shown in recent years that within the spectrum of the silent nociceptive afferents in human cutaneous nerves there is probably a small population (approx. 5% of all C Fibers) of afferents, which can be excited particularly easily by local application of histamine, with severe itching occurring at the same time. In relation to practically all other stimuli, these receptors remain silent, with the exception of substances that also cause itching, v. a. Prostaglandin E 2, acetylcholine and serotonin. This finding speaks for the existence of independent itch receptors, especially since spinal neurons have now been found that are specifically innervated by these afferents. G A small subpopulation of dumb nociceptors in human skin appears to be specific itch receptors whose spinal endings are switched to specific neurons. 3 Central nociceptive systems.3.1 Processing of noxious signals in the spinal cord and medulla oblongata Spinal transmission and processing in the spinal cord the nociceptive afferents end at neurons of the dorsal horn. These nerve cells are the starting point for the anterior strand tracts detailed in Chapter 14 (Section 14), which ascend in the direction of the brainstem in order to unite with the nociceptive afferents from the head region, largely derived from the trigeminal nerve, on the way to the thalamus (. Fig. 10a ,. Fig b and the associated text in Sect.). Other neurons are involved in motor and vegetative reflex arcs (motor and vegetative components of pain, Section 1.2). Some of these reflexes are organized spinally, others are mediated by supraspinal reflex arcs (Chaps. 9 and 13). (The transmitters and modulators involved in spinal and supraspinal nociceptive processes are presented in connection with central sensitization in Sect. 4.3.) G The nociceptive afferents are switched in the spinal cord and brain stem to neurons that are involved in motor and vegetative reflexes and / or project to the thalamus and cortex. Transmitters and receptors of nociceptive synaptic transmission in the spinal cord and medulla oblongata. Fig. 11a shows a spinal neuron at which a nociceptor (C-fiber) and an inhibitory interneuron end. The nociceptive presynaptic ending releases glutamate when activated. In addition, any co-transmitters that may be present, e.g. B. released the excitatory neuropeptides substance P and CGRP (Sect.). On the postsynaptic side, glutamate activates ionotropic NMDA and non-nmda receptors (AMPA and kainate receptors; Section) as well as metabotropic glutamate receptors (Section 4.3.3). The excitatory neuropeptides (substance P, CGRP) strengthen the synaptic transmission through glutamate. Inhibitory interneurons release GABA and / or glycine or inhibitory neuropeptides, in particular opioid peptides such as enkephalin (Enk), at their synapses. The postsynaptic membrane of the spinal cord cell has receptors for these mediators (. Fig. 15.8c, Sect.). Their activation counteracts the exciting processes.

12 352 Chapter Nociception and Pain. Fig..10a, b. Pathways and switching points of the central nociceptive system. Schematic overview of the course of the ascending nociceptive pathways a and the descending pathway systems that modulate the nociceptive influx b. Of the ascending orbital systems, only the spinothalamic tract and the trigeminal thalamic tributaries connected to it are shown. Other pathways involved in the ascending conduction of nociceptive information (e.g. spinoreticular tract, spinocervical tract) have been omitted for the sake of simplicity. The specific thalamocortical pathways originate from the lateral thalamus; they mostly end in the somatosensory cortex. The efferents of the medial thalamic nuclei are more diffuse. They not only end in large areas of the frontal cortex, but also run to subcortical structures, especially the limbic system (not shown, nor the strong reticular inflows of these nuclei). The descending systems exert their influence predominantly on the spinal level (or on the corresponding trigeminal structures, not shown). The inset figure shows the position of the brain stem sections in a side view of the brain stem: 1 cranial edge of the lower olive, 2 middle of the pons, 3 lower mesencephalon. PAG periaqueductal gray (central cave gray); NRM Nucleus raphe magnus G The excitatory transmitter of nociceptive afferents is glutamate, which activates both NMDA and non-nmda (AMPA) receptors. The postsynaptic inhibition is transmitted by GABA and glycine. Exciting and inhibiting neuropeptides are often colocalized. Box.2. Gate control theory of the spinal processing of nociceptive information As with any other sensory system, nociceptive information can already be influenced at the first synapses in the spinal cord and brain stem. How this happens in detail is still largely unknown (Section 3.3, remarks on the endogenous pain control systems). The gate-control theory proposed by Melzack and Wall in 1965 was a suggested explanation for the functioning of a spinal pain-relieving system. She postulated as one of her essential statements that the centripetal projecting dorsal horn neurons of the nociceptive system are inhibited by the excitation of thick non-nociceptive afferents (gate closed) and activated by the excitation of thin nociceptive afferents (barrier open). This inhibition was supposed to be generated in the substantia gelatinosa of the dorsal horn of the spinal cord and this was the critical point of the theory only to be transferred to the thin nociceptive afferents via a presynaptic inhibition mechanism. This hypothesis could not be confirmed experimentally, its essential postulates were even refuted. The (postsynaptic) inhibitory effect of thick non-nociceptive afferents on thin nociceptive afferents has not yet been clearly proven. A second statement of the gate control theory was that the spinal inhibition mechanisms of nociception in the substantia gelatinosa can also be activated by descending inhibition systems and that in this way the nociceptive information is already subject to centrifugal control at the spinal level. The existence of such descending inhibitory systems is now considered to be certain, not only in the nociceptive, but also in all other somatosensory systems (. Fig. 10b,. Fig. In Sect.). The gate control theory in the narrower sense is only of historical interest. However, it remains to her essential merit to have pointed out very early on that the nociceptive influx into the spinal cord can already be considerably modulated at the level of the first central neurons by local and descending influences..3.2 Processing of noxious signals in the thalamus and cerebral cortex The lateral thalamocortical system Nociceptive neurons in and below the ventrolateral complex of the thalamus are excited via the spinothalamic tract, and they project into the somatosenso-

13 .3 Central Nociceptive Systems 353. Fig..11a c. Synaptic excitation and inhibition on a nociceptive neuron of the spinal cord. The neuron receives an exciting input from a nociceptor (C-fiber) and an inhibitory input from a spinal interneuron. Shown below are receptors for these mediators in the postsynaptic membrane. Glu glutamate, NP neuropeptide, G s stimulating G protein, G i G protein with inhibitory effect, Enk enkephalinic cortex. These thalamic and cortical cells make up the lateral system. The activation of the lateral system is responsible for the sensory-discriminative pain component. At the same time, tactile, nociceptive and other sensory information is integrated into an overall picture in the sensory cortex, i.e. H. Toxic information is classified in the entirety of our image of the body and the environment. About 10 times more fibers than lead from the thalamus to the cortex run from the cortex to subcortical and limbic connections: Many lead from S1 to S2 and from there to the islet and the cingulate gyrus, where the emotional components of pain arise (Box. 3). Box.3. Imaging of pain The various pain components in the human brain can be objectified using imaging methods (fmrt, PET, Chapter 20). In the illustration, the person was given a longer, painful pressure stimulus on a finger and the brain activation was measured with fmrt. The primary somatosensory area S1 is activated contralaterally, which represents the sensory-discriminatory component of pain; Furthermore, the secondary somatosensory cortex S2 (top left), the subjective-psychological correlate of which has been little researched (presumably violation of the normal body pattern through pain stimuli), the anterior island (center), which reflects the negative affective component, and finally the posterior part of the anterior gyrus cinguli (ACC, top right), which reflects attention and affective avoidance. The recordings were made by Dr. Karen Davis, University of Toronto.

14 354 Chapter Nociception and Pain The Medial Thalamocortical and Limbic Frontal System Nociceptive neurons in the posterior complex and in the intralaminar complex of the thalamus project to associative cortical areas. Together with the corresponding cortex areas, they form the medial system. This is e.g. B. responsible for the affective pain component. The insula of the cortex is held responsible for an interaction between sensory and limbic activities. The anterior cingulate gyrus in particular is used for attention and response selection in the event of noxious irritation. The prefrontal cortex is involved in many aspects of affect, emotion, and memory. At the cortical level, the activity of the nociceptive system is related to numerous other neuronal functions. G The sensory-discriminative pain component arises from activation of the lateral thalamocortical system. In the medial thalamocortical system with the prefrontal and insular regions, the affective pain components, memory formation and attention reactions to pain stimuli are generated and thus to keep these systems in an optimal working area. The existence of these endogenous pain control systems (more precisely, but more cumbersome: endogenous control systems of central nociception) can e.g. This can be recognized, for example, by the fact that electrical stimulation of certain supraspinal areas (such as the central gray cave) leads to analgesia in animals and humans (7, below, »electron anesthesia«) .. Figure 10b shows descending pathways that emanate from the cerebral cortex and core areas in the brain stem . Periaqueductal gray (PAG, central cave gray) plays a key role. Its stimulation can produce total analgesia (7 above and "electro narcosis" below), which is mediated by opiodergic fibers that project largely to the nucleus raphe magnus, NRM, and possibly also directly into the spinal cord. Fibers descend from the NRM in the dorsolateral funiculus to the spinal cord. In addition to its projections in the brain, the Locus coeruleus also has projections on the spinal cord. The descending fibers end v. a. on spinal interneurons, on which they form inhibitory synapses. An important function of these descending fibers is the tonic inhibition of the spinal cord cells. The descending inhibition raises the threshold of the spinal cord neurons and their responses to noxious stimuli are weakened. The tonic descending inhibition, together with segmental inhibitory interneurons, represents an endogenous antinociceptive system that keeps pain at bay. G Descending pathways, as endogenous pain control systems, modulate spinal and supraspinal nociceptive processing. The most important node is the central gray cave, the electrical stimulation of which can cause total analgesia. Pain inhibition via endogenous opiates It is well known that opiates inhibit the sensation of pain without significantly influencing the other sensory modalities. This targeted action of opiates is based on the existence of specific opiate receptors on the neurons of the nociceptive system, which exist because the body itself, as part of its internal pain control system, forms opiate-like substances that serve as ligands for these receptors. Box.4. Nociception and pain during sleep and under anesthesia We only feel pain when the thalamocortical system is awake. In deep sleep (Chapter 22), nociceptors and nociceptive spinal cord cells can be activated and forward nociceptive information to the thalamus via ascending pathways, but further processing in the thalamus is blocked so that no conscious pain is generated. However, strong pain stimuli can activate the ascending reticular system so that we are awakened. Most anesthetics commonly used today (e.g. propofol) block the thalamocortical system and generate theta-delta sleep via stimulation of the GABAerger systems. The loss of consciousness is caused by the inhibitory influence on the cortex, the pain inhibition, depending on the anesthetic, by inhibiting the thalamus or other sections of the pain pathways. Under anesthesia, the conscious perception of pain stimuli is suspended. In contrast, the nociceptive processes in primary afferents and in the spinal cord are often not switched off. In order to suppress the nociceptive processes on these levels, a modern anesthetic always consists of a combination of pain therapy (e.g. spinal cord anesthesia) and switching off the consciousness.

15 .4 Pathophysiology of Nociception and Pain 355 These endogenous ligands, e.g. B. the pentapeptides methionine and leucine enkephalin, are released in the nervous system, bind to the opiate receptors and thereby produce hypo- or analgesia. The administration of the opiate antagonist naloxone neutralizes their effect, peptidases break them down in vivo. Methionine-enkephalin is a component of the polypeptide beta-endorphin, leucine-enkephalin is contained in the polypeptide dynorphin. Both polypeptides also have an analgesic effect; v. a. Dynorphin has a much stronger effect than the enkephalins. At least 3 subtypes of opiate receptors, namely the μ-, δ- and κ-receptors, are known, which differ in their sensitivity profile for opiates and for the various endogenous ligands. Therapeutically used opioids have a v. a. at μ-receptors to which the endorphins and endomorphins also bind. G The body's own opiates are ligands of the body's own opiate receptors on the neurons of the endogenous antinociceptive system. Release of the body's own opiates therefore leads to pain inhibition. Electronic anesthesia An electrical stimulation of the entire brain can lead to anesthesia and analgesia ("electronic anesthesia"). This seems to start from circumscribed areas of the central gray cave, because local electrical stimulation of these areas leads to deep analgesia in animal experiments, which is referred to as stimulation-produced analgesia, SPA. Particularly important points seem to be the nucleus raphe magnus and the nucleus paragigantocellularis (or magnocellularis) of the formatio reticularis, because direct descending pathways lead from these core regions into the spinal cord, the activation of which may inhibit the transmission of nociceptive information in the dorsal horn (see Box 4 ). Microinjections of morphine into the central gray cavity, as well as electrical stimulation, result in marked analgesia. This indicates the close connection between SPA and opiate analgesia. Other structures that are closely correlated with the SPA, for example in the reticular formation (7 above), are also clearly sensitive to opiates. It is therefore likely that the analgesic effects of SPA and exogenous and endogenous opiates are mediated through the same neuronal systems. The most interesting consequence of this conclusion is that the point of attack on the nociceptive signals not only for SPA but also for opiate analgesia must be in the dorsal horn of the spinal cord. Apparently the analgesic effects from the brain stem are mediated via several descending pathways (. Fig. 10b), whereby monoaminergic transmitters, in particular serotonin, norepinephrine and dopamine are involved (7 above) .. 4 Pathophysiology of nociception and pain.4.1 Pain caused by excitation Acute Projected Pain from Nociceptive Nerve Fibers Not all nociceptive impulses originate in the endings of the nociceptors. So it happens B. with strong mechanical irritation of the ulnar nerve at the elbow to abnormal sensations in the supply area of ​​this nerve (. Fig. 12). Obviously, the activity triggered at the elbow in the afferent fibers is projected by our consciousness into the supply area of ​​these afferent fibers, since normally such sensory impulses come from the sensors of this supply area. The interpretation of the sensations (tingling, etc.)We find it difficult because the impulse pattern that occurs through direct mechanical stimulation of the nerve fibers does not normally occur. Projected sensations can, in principle, occur within any sense sensation, but only the projected pain is clinically meaningful. Such pain often occurs, for example, when the spinal nerve is compressed as part of an acute intervertebral disc syndrome. The pain sensations that occur in nociceptive fibers due to the centripetal impulses are projected into the supply area of ​​the irritated spinal nerves. (In addition, local pain can of course also occur.) In the case of projected pain, the location of the effect of the noxious agent is not identical to that of the pain sensation. Neuralgic Pain Far more important than acute projected pain of the type just described is projected pain caused by continued irritation of a nerve or a back root. Such chronic nerve damage leads to "spontaneous" pain, which is often wavy. Fig..12. Development of the projected pain (schematic, details 7 text)

16 356 Chapter Nociception and Pain or Attack. As is to be expected from the projected pain, they usually remain limited to the supply area of ​​the diseased nerve or the damaged root. This pain caused by pathophysiological impulse formation on nociceptive fibers (not on the nociceptors) is characterized by the terms neuralgia or neuralgic pain. A special form of neuralgic pain is the complex regional pain syndrome ("complex regional pain syndrome", CRPS) in which the sympathetic nervous system is involved. It is described in Box 6.2 in Sect. In addition to the vegetative disorders (swelling, changes in blood flow, extreme perspiration), cortical and subcortical reorganization occurs, comparable to deafferentiation in amputation (Section 4.3). G Activation (through pressure, injury, etc.) of nociceptive afferents leads to pain that is projected into the innervation area of ​​the nerve fibers. Chronic forms of pain after nerve injuries can be particularly excruciating..4.2 Pain of spinal and supraspinal origin Transferred pain Noxic irritation of the viscera is often not perceived as pain, or not only on the internal organ, but also on the surface of the skin, although typical for each internal organ Have the skin areas indicated to which the intestinal pain is transmitted (e.g. inside of the left arm in angina pectoris). These skin areas are referred to as head zones (. Fig. 13a, b). Because of this connection, transferred pain is often an important diagnostic aid. The assignment of the head zones to the viscera is due to the fact that the skin afferents of each posterior root of the spinal cord innervate a circumscribed area of ​​skin. This area of ​​skin is called a dermatome (. Fig. 13c). As can be seen in the figure, however, neighboring dermatomes overlap considerably because the dorsal root fibers bundle into the periphery as they grow. The dermatomes, however, are well preserved despite all the bundling of the primarily afferent fibers. The same is true for the spinal afferent innervation of the abdominal viscera. So it happens that the head zone of an internal organ, e.g. B. of the heart or the stomach, is formed by precisely those dermatomes whose associated spinal cord segments supply this organ in an afferent manner .. Fig..13a c. Human head zones and dermatomes for the chest and stomach area. a, b Head zones (superficial hyperalgesic zones) for the specified viscera. The spinal nerves through which the visceral afferents enter the spinal cord from the organs are also indicated. The head zones are represented in different sizes in the literature (cf. a with b, depending on the type of observation. C human dermatomes. The innervation areas of the posterior roots of successive spinal cord segments are indicated alternately in one half of the body)

17 .4 Pathophysiology of Nociception and Pain 357. Fig. 14. Pathways of Transferred Pain. It is shown on the left that nociceptive afferents from the intestines partly end at the same neurons of the dorsal horn as nociceptive afferents from the skin. On the right it can be seen that the same nociceptive afference can occasionally supply both superficial and deep tissue. The origin of the transmitted pain is probably based on how. Fig. 14 shows that, on the one hand, nociceptive afferents from the skin and deep tissues converge on the same cells of origin of the ascending nociceptive pathways (left half of the picture) and, on the other hand, axon collaterals of such primary nociceptive afferents are already in 2 or more collaterals in the area of ​​the spinal nerves branch, which then innervate superficial and deep structures (right half of the picture). Excitation of the central nociceptive neurons is interpreted as pain in the periphery, since, as with the other important sensory systems, the brain has learned that the stimuli come from outside the body and not from the internal organ. As a further consequence of the central convergence and divergence of nociceptive afferents shown in Fig. 14, hyperpathy (7 below) or hyperesthesia (7 below) of the skin in the affected dermatome can occur. These are based on the fact that the excitability of the spinal interneurons is increased by the nociceptive impulses from the deep tissues, so that a skin stimulus leads to a stronger activation compared to the normal state. Finally, it should be remembered that neuralgic pain can of course also appear as transferred pain or occur together with a transferred component. G Noxic irritation of the viscera often does not hurt or only hurts the internal organ, but also in the head areas of the skin. This is due to the spinal segmental convergence of nociceptive afferents from the intestines and the associated dermatomes. Central pain Functional disorders or lesions of the spinal and supraspinal nociceptive systems can, e. B. by the impairment or failure of the endogenous pain control systems (Sect. 3.3) lead to increased excitability and spontaneous activity in the ascending nociceptive thalamocortical systems, which can cause considerable pain. This pain is known as central pain. Well-known examples are the pain of anesthesia dolorosa after tearing back roots or the thalamic pain after damage to sensory thalamic nuclei. In many cases, damage to central nervous structures is not painful (e.g. after a stroke or in the case of brain tumors) if these lesions are outside the pain analyzers (see Box 5). G If the central nervous system is damaged, the impairment of the endogenous pain control systems can lead to severe pain conditions (central pain), as this disinhibition of the central noviceptive system leads to increased excitability and spontaneous activity. Box.5. Frontal lobotomy After damage to the prefrontal cerebral cortex, pain sensitivity, v. a. the emotional-affective component and the cognitive component (assessment of the threat of the pain stimulus). In the past, this was often used therapeutically by surgically severing the thalamofrontal tracts in chronic pain (frontal lobotomy). This drastic procedure is practically no longer used today thanks to better pain therapies. The sensory discrimination of the nociceptive stimuli (e.g. the distinction between sharp and blunt stimuli) is retained after a frontal lesion. The pain stimulus only loses its vital-personal meaning.

18 358 Chapter Nociception and Pain.4.3 Sensitization and plasticity of the central nociceptive system Central sensitization through nociceptor sensitization Central nociceptive neurons show a considerably increased activity in inflammation and other tissue lesions. This central sensitization is a consequence of the sensitization of the nociceptors under these conditions described in Sect. 2.1. An example shows. Fig..15. The neuron shown had a high-threshold receptive field under control conditions (green area in. Fig. 15b), and pressure on the knee joint also led to discharges (blue curve in. Fig. 15a). Pressure on the ankle and paw, on the other hand, was "unsuccessful". After a knee joint inflammation was triggered, the responses of the spinal neuron increased not only to noxious irritation of the knee joint, but also to irritation of the ankle and paw (red and yellow curves in Fig. 15a). The peripheral receptive field of the neuron also increased and its threshold sank into the non-noxic area (orange field in. Fig. 15c). The central sensitization is triggered by the increased activity of the sensitized nociceptors and the associated increased release of glutamate and colocalized neuropeptides (Section 3.1). It then continues to strengthen itself, although the decisive mechanisms of this process are not yet fully understood. Most important seems to be the strong release of glutamate from the nociceptive presynaptic endings, which leads to an opening of the NMDA receptors (section), which causes particularly intense neuronal excitation (see section). Ketamine, a selective NMDA receptor antagonist, therefore inhibits pain at the spinal cord and brain level, but also leads to impaired consciousness due to its cortical effect. G The central nociceptive system is plastic: When tissue inflammation occurs, its neurons become overexcitable. Central sensitization has peripheral and central causes. Glutamate and its receptors play a key role in this, but other transmitters are also involved. Pain phenomena as a result of central sensitization Depending on the type and extent of peripheral and central sensitization, clinical pain occurs, the manifestations of which are described as follows: 4 Allodynia is a sensitivity to pain to normally non-noxious stimuli (harmless example: oversensitivity to touch when sunburned ) .. Fig..15a c. Plastic changes in the nociceptive system with inflammation. a Development of hyperexcitability (central sensitization) in a nociceptive neuron from the spinal cord of an anesthetized cat in the course of experimental knee arthritis. The curves show the responses (number of action potentials) to noxious stimuli of the knee joint, the ankle joint and the paw before (negative times) and after the initiation of arthritis (inflammation of the joint by injection of kaolin and carrageenan). The original receptive field of the neuron in the knee joint and the surrounding deep tissue can be seen in b: the neuron could only be excited from there by noxious pressure. c The receptive field increased in the course of the arthritis, at the same time the neuron was now excitable by non-noxious pressure 4 In contrast, hyperalgesia denotes an increased sensitivity to noxious stimuli. Clinically, a distinction is made between primary hyperalgesia in the area of ​​damage and secondary hyperalgesia in the surrounding healthy tissue. 4 Hyperpathy is a pain syndrome that is characterized by a delayed onset, increased response and an after-response that persists over the stimuli. It is particularly evident in the case of repetitive irritation. Decreases in sensitivity to pain, i.e. hypo- or analgesia, usually only occur in connection with disorders or failures of other sensory modalities. For example, in the simplest case, the severing or blockage (e.g. with novocaine) of a cutaneous nerve is used for analgesia of its supply area, but also for the failure of the other skin sensory modalities, i.e.

19 .4 Pathophysiology of nociception and pain 359 esthesia, lead (with regard to congenital insensitivity to pain 7 case 1 of the introduction). G Allodynia, primary and secondary hyperalgesia and hyperpathia signal sensitization in the peripheral and central nociceptive system. Isolated hypo- and analgesia are very rare. Phantom pain The phantom pain can be seen as a model system for the formation of a pain memory. In arm or hand amputees who had pain before or during the amputation, phantom pain occurs in 40-70% of cases in the amputated limb (depending on the cause of the amputation), in leg amputees and breast amputated women somewhat less, as these body regions are less large on the cortex are represented (sensory homunculus, Fig.). Phantom pain also occurs in highly paraplegic people who do not have any nociceptive influx into the brain. Phantom pain often occurs immediately after amputation and can remain excruciatingly stable over a lifetime. Chordotomy (Section 6.2) does not eliminate them, which shows that they cannot be traced back to peripheral changes in nociception. Peripheral nociceptive irritation (cold, heat, tension due to stress) can trigger and intensify phantom pain, which also explains why local anesthesia of the residual limb can relieve or interrupt the pain for many patients in the short term. G Phantom pain and pain after cross-sectional lesions must arise in the brain, since they persist even without afferents to the brain. Receptive fields after amputation In animal experiments, it has already been shown hours after a finger is amputated that the neurons of the finger region and those of the hand region in the somatosensory cortex react more strongly to somatosensory and nociceptive stimulation in the body regions near the amputation (Fig.). Your receptive field spreads into the deafferent regions. In individual animals (monkeys), even 12 years after the amputation, far removed from the receptive field of the deafferentiated limb in parietal regions, an increased discharge after irritation in ipsilateral, non-deafferented body regions could be detected. If you sew two fingers together, the receptive cortical fields of the two fingers grow together after a short time (days) and irritation of one (former) finger triggers the same response of the neurons in both receptive fields (syndactilia). Fig ... Cortical reorganization in an arm amputee with severe phantom pain. The brain of a patient with chronic phantom pain recorded with the help of magnetic resonance imaging (left = front, right = back). The circles each identify the representations of the respective body part measured with the magnetoencephalogram. Above: the hemisphere contralateral to the amputated arm, below the hemisphere contralateral to the intact arm. If the lip on the side of the amputated (deafferentated) arm is irritated, there is additional activation in the area of ​​the amputated region (hand, D1 D5), i. H. the lip and face representation has "immigrated" into the deafferent, "empty" region. The extent of this immigration ("invasion") is exactly proportional to the phantom pain. Below: the hemisphere is shown contralateral to the intact arm with the usual arrangement of the sensorimotor homunculus: lip and face inferior and above the hand with the thumb and then the remaining fingers. Above the "amputated" hemisphere with the hand region mirrored by the intact hemisphere and the lip region that has grown into it (symbolized by a red arrow) G After amputation or deafferentation, animal experiments show massive changes in the discharge behavior of the nerve cells in and outside the receptive field. Cortical reorganization after amputation. Fig. Shows the cortical reorganization of an arm ampute with severe phantom pain. The cortical source of magnetic fields (MEG, Chapter 20) after tactile stimulation of the ipsilateral and contralateral lip area and the thumb of the intact hand was compared. The dipoles (sources) of activity after lip stimulation (on the sensory cortical homunculus adjacent to the thumb, Chapter 14) contralateral to the amputation are found where the thumb is represented (symbolized by the red arrow). The lip area has, symbolically speaking, grown into the thumb area. Often the patients also report sensations and pain in the phantom limb when irritated in the stump, shoulder and face area ("remapping" or new mapping). From Kaas JH (1991). Courtesy of the Annual Review.

20 360 Chapter Nociception and Pain From Flor H, Birbaumer N (2000). Courtesy Lippincott Williams & Wilkins .. Fig.17. Relationship between phantom pain and the extent of cortical reorganization. Phantom pain was measured using a special questionnaire. Each triangle represents a patient, with the ordinate the extent of phantom pain (back triangles). Front triangles: extent of reorganization, measured in cm. Fig. 17 shows the extent of phantom pain in 13 arm amputees and the size of this cortical reorganization (measured in centimeters) between the location on the somatosensory cortex where the lip should be and where it is currently located. One can clearly see the closeness of the connection. One can conclude from this that cortical reorganization through activation of deafferentiated brain regions in the cortex could be a basis for pain memory (Box 6). G The cortical reorganization in the case of amputation or deafferentiation of the hand consists of shifting the facial area into the hand area. This leads to sensitization and pain. Motor reorganization The failure of a limb or one side of the body (after a stroke) naturally also means that there is no proprioceptive afferent influx from muscles and tendons (Chapter 13), which could also contribute to pain-increasing reorganization, since there is no pain-relieving influx from myelinated Aβ fibers.The elimination of motor functions leads to a motor reorganization of the sensorimotor brain areas in parallel to the sensory reorganization: With non-invasive transcranial magnetic stimulation (Chapter 20) of the motor cortex, one can test the excitability of the individual cortical areas and the associated α-motor neurons in the spinal cord. After amputation, there is consistently increased excitability in and around the deafferentated brain area for the hand or leg. The same can be found after paraplegia, whereby tactile and touch sensations can also be triggered in these cortical areas, which shows that this is a central reorganization. G When the sensory areas are reorganized, the motor areas usually also reorganize. Functional use of motor units can therefore cancel out sensory reorganization. Box.6. Asynchronous tactile stimulation for the treatment of phantom pain Chronic phantom pain after amputations can be traced back to a reorganization of the cortex caused by excessive nociceptive influx before, during or immediately after the amputation, as described in Section 4.3. Fig. And 17, has been described. The cortical representation of the deafferent limb (e.g. hand, arm) connects with the representations of the shoulder and face adjacent to the somatosensory homunculus. In order to break this pathological associative connection again, the stump region and lip are stimulated asynchronously and tactilely every day for 3 hours for weeks many 1000 times (Fig.). This gives the brain the information: "Arm-hand and face do not belong together." After weeks, the reorganization shown in Fig. 17 and the pain in the somatosensory cortex recede. This is one of the many uses of the Hebb rule of associative learning that we will discuss in Chap. 25 describe. But the use of a neuromuscular prosthesis with which one can grasp functionally improves the phantom pain, in contrast to a cosmetic prosthesis without function. The sensible use of the limb is the decisive stimulus in this case. Literature: Huse E, Preissl M, Larbig W, Birbaumer N (2001) Phantom limb pain. The Lancet 358: From Huse E, Preissl M, Birbaumer N (2001). Courtesy of Elsevier.